Factorial Study Design 07/18/12

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1 Disclaimer: The following information is fictional and is only intended for the purposes of illustrating key concepts for results data entry in the Protocol Registration System (PRS). Example Factorial Study Design (A Phase III Double-Blind, -Controlled, Randomized, Factorial Design Trial of Two Doses of and Supplement in Patients with Heart Failure) Methods Study Design This multicenter, double-blind (subject/investigator), randomized, placebocontrolled interventional, factorial design study enrolled patients hospitalized with Heart Failure from research sites in the United States: Brigham and Women's Hospital at Harvard Medical School (Boston, MA), Children's Hospital Montefiore (Bronx, NY), Duke University Medical Center (Durham, NC), Thomas Jefferson University Hospital (Philadelphia, PA), University of Texas Medical Branch at Galveston (Galveston, TX). Patients entered a run-in period during which they received mg tablet once daily and placebo Softgel Supplement for 2 months. Eligible patients who completed run-in were then randomized in a 2x2 factorial blinded design between 80 mg tablet once daily versus mg tablet once daily and Softgel Supplement (900 mg EPA, g DHA) once daily versus placebo Softgel Supplement once daily (See Table 1). The protocol and informed consent documents were reviewed and approved by a recognized ethics review board at each study facility. The study was performed in accordance with the Declaration of Helsinki. Table 1. 2x2 Factorial Design Randomization mg 80 mg Total Supplement 100 participants a 100 participants b participants c 100 participants d 200 Total a Reasons for drop out: 2 Lack of Efficacy; 1 Physician Decision; 1 Pregnancy; 2 Did Not Follow Protocol; 10 Died; 17 Adverse Event b Reasons for drop out: 1 Lack of Efficacy; 9 Died; 16 Adverse Event c Reasons for drop out: 3 Lack of Efficacy; 1 Physician Decision; 1 Moved Out of Country; 10 Died; 16 Adverse Event d Reasons for drop out: 1 Lack of Efficacy; 1 Did Not Follow Protocol; 8 Died; 16 Adverse Event 1

2 Patients Inclusion Criteria Patients, regardless of gender, at least 18 years of age and hospitalized for the management of Class III or IV Heart Failure (HF) using the New York Heart Association (NYHA) classification 1 or diagnosed with Class III or IV Heart Failure within 72 hours of hospitalization for another reason were eligible for the trial. Patients were also required to have a sufficient level of education to understand study procedures and be able to communicate with site personnel. Exclusion Criteria Patients having received an antihistamine for more than 2 days prior to randomization or those unable to be treated by were excluded. Additional exclusion criteria included history of acute liver injury (e.g., hepatitis) or severe cirrhosis; pregnancy or breast-feeding; allergy to or Supplement; and participation in a study of an investigational medication within the past 30 days. Primary Endpoint The motivation for this study came from indications in the literature that supplements may have a protective and/or ameliorative clinical effect on heart failure. Since statins are frequently prescribed for certain patients with heart failure, it was a primary goal to see if had any short-term protective clinical effect for patients receiving statins and secondarily whether the effect, if any, had an interaction with the statin dose. The primary composite endpoint was rehospitalization for heart failure or death from any cause during the period from randomization to day 30 by intervention, summing all participants who received each intervention regardless of the paired combination (i.e., mg; 80 mg; Supplement; and ). Rehospitalization and fatal events within 30 days after randomization were reviewed and categorized by an independent, blinded clinical-events committee. The following criteria were required for rehospitalization events to be classified as due to heart failure: typical clinical manifestations of worsening heart failure and the addition of (or increase in) interventions specifically for worsening heart failure with an intravenous pharmacologic agent, or mechanical or surgical intervention or ultrafiltration, hemofiltration, or dialysis specifically for management of persistent or worsening heart failure. Hospitalized patients who remained in the hospital at 30 days because of heart failure were counted as being rehospitalized for heart failure in the analysis of the primary composite end point. Secondary Endpoints Secondary endpoints included the composite endpoint of rehospitalization for heart failure and death from any cause during the period from randomization to day 30 by randomization group; and safety. Safety Safety was assessed by the number of adverse events (AEs). AEs were collected by systematic assessment using terms from the Medical Dictionary for Regulatory Activities (MedDRA), version.1. Results Of the 600 patients screened during the run-in period between July 1998 and September 2007, 67% (N = 400) were randomized to the four intervention groups (Table 1). The last patient completed in May Participant characteristics by randomization and by intervention are shown in Tables 2 and 3, respectively. 2

3 Table 2. Demographic Characteristics of Participants by Randomization Group Age in Years Mean (SD) Gender Male Female NYHA HF Class Class III Class IV Heart Failure Diagnosis Pre-hospitalization During hospitalization SD = Standard Deviation mg + 80 mg + mg + 80 mg (4.7) 64. (.0) 64.0 (4.8) 64.6 (.1) Total n = (4.9) Table 3. Demographic Characteristics of Participants by Intervention Age in Years Mean (SD) Gender Male Female NYHA HF Class Class III Class IV Heart Failure Diagnosis Pre-hospitalization During hospitalization mg 80 mg Total n = (4.7) 64.6 (.2) 64.2 (4.9) 64.3 (.0) 64.2 (4.9) SD = Standard Deviation; NYHA HF = New York Heart Association Heart Failure

4 The primary and secondary clinical endpoints are reported in Table 4. Statistical analysis was performed with chi square, and a p-value<0.0 was considered statistically significant. There was no significant improvement for rehospitalization or death when analyzed by intervention (p = 0.96) or by randomization group (p = 0.97). Cumulative probabilities for the primary clinical endpoint for the and analysis populations were estimated using Kaplan-Meier product-limit method and Greenwood s formula for 9% confidence intervals. For, the estimated cumulative probability of rehospitalization or death at 30 days was 0.28 (9% CI: 0.17 to 0.39). For, the cumulative probability was 0.26 (9% CI: 0.1 to 0.37) Adverse events are shown in Table. If a participant experienced the same serious adverse event more than once, then each event would have been recorded as a distinct event. However, no participant experienced the same serious adverse event more than once. If a participant experienced the same non-serious adverse event more than once, then it was only recorded as one adverse event. References 1 eartfailure/aboutheartfailure/classes-of-heart- Failure_UCM_306328_Article.jsp#.T1eG2vW- 32k Table 4. Primary and Secondary Clinical Endpoints from Randomization through Day 30: Rehospitalization for Heart Failure and Death from Any Cause Primary mg: no./total no. (%) 3/200 (26.) 80 mg: no./total no. (%) 49/200 (24.) : no./total no. (%) 2/200 (26.0) : no./total no. (%) 0/200 (2.0) Secondary mg + : no./total no. (%) 27/100 (27.0) 80 mg + : no./total no. (%) 2/100 (2.0) mg + : no./total no. (%) 26/100 (26) 80 mg + : no./total no. (%) 24/100 (24) 4

5 Table. Adverse Events through Day 30* mg + 80 mg + mg + 80 mg + Total**/Total Other 30/20 26/22 27/27 27/28 Myocardial Infarction** Death** Palpitations 8 1 Ventricular tachycardia Chest pain Hyperglycemia Hyperlipidemia Hemorrhagic stroke** Hemorrhagic transformation stroke** Dizziness Headache Dyspnea Hypertension Ischemia *If a participant experienced the same serious adverse event more than once, then each event was recorded as a distinct event. If a participant experienced the same non-serious adverse event more than once, then it was only recorded as one adverse event. **Event classified as Serious (i.e., Death or Resulting in Death, requiring either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect).